PDA Cell Research Articles

Abstract A066: nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer

Abstract The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression. Citation Format: Audrey M Hendley, Sudipta Ashe, Atsushi Urano, Martin Ng, Tuan A Phu, Xianlu Laura Peng, Changfei Luan, Anna-Marie Finger, Gun Ho Jang, Natanya R Kerper, David I Berrios, David Jin, Jonghyun Lee, Irene R Riahi, Oghenekevwe M Gbenedio, Christina Chung, Jeroen P Roose, Jen Jen Yeh, Steven Gallinger, Andrew V Biankin, Grainne M O’Kane, Vasilis Ntranos, David K Chang, David W Dawson, Grace E Kim, Valerie M Weaver, Robert L Raffai, Matthias Hebrok. nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A066.

Abstract 3541: Systematic assessment of the mechanism of action landscape of glue compounds

Abstract We have recently completed a large-scale project to elucidate the Mechanism of Action (MoA) of clinically relevant compounds in over twenty tumor specific contexts. Many novel, translationally relevant findings have arisen from this work, including (a) the identification of context-specific inhibitors of many proteins considered to be poor pharmacologic targets—including transcription (co-)factors and undruggable signaling proteins; (b) graph theory-based elucidation of drug polypharmacology; and (c) identification of MoA overlap between previously unrelated drugs. However, a limitation of the study is it relies on the existing repertoire of small-molecular inhibitors that is heavily biased towards specific target classes. Compounds that inhibit master regulators (MR) of tumor state are missing or under-represented. In this new project, we explore an extra molecular space of “molecular glues”, as they might be more effective modulators of MRs. Similar to our prior oncology drug study, we will leverage the automated PLATE-Seq technology and the VIPER algorithm to characterize compound MoA in a proteome-wide fashion. Specifically, we will first generate genome-wide RNA-Seq profiles of patient-matched cell lines using a panel of ~150 glue compounds, including a subset of them named PROteolysis TArgeting Chimeras (PROTACs) that were designed to degrade therapeutic targets by recruiting them to E3 ligases. We will analyze the PLATE-seq perturbational profiles with a set of complementary algorithms including the VIPER, which, akin to a multiplexed, tissue-specific gene reporter assay, can accurately measure the differential activity of over 6,000 regulatory/signaling proteins, by assessing the enrichment of their transcriptional targets in differentially expressed genes. Current effort of this project is focused on six PDA cell lines including three MAPK-pathway dependent (M+) and three MAPK-pathway independent (M-) contexts, each one representing the gastrointestinal lineage state (GLS), morphogenic state (MOS), and acinar to ductal metaplasia-like state (ALS). Using this data, we explore similarity-based connections between PLATE-seq perturbational profiles and the Connectivity Map (CMAP) that contains transcriptional consequences of chemical and genetic perturbations. We will also compare PLATE-seq perturbational profiles to tissue-specific differential expression signatures that distinguish cell lines sensitive to compounds in the Cancer Therapeutics Response Portal (CTRP) and Broad Repurposing Hub, each of which houses results from exposing hundreds of compounds exposed to dozens to hundreds of cell lines. Taken together, the data and analyses will help understand MoAs and polypharmacologies/off-targets of molecular glues, which also serve to enable interpretation and prioritization of new candidate MoA for molecular glues by comparing them to compounds with known targets and MoAs. Citation Format: Lucas ZhongMing Hu, Charles Karan, Andrea Califano. Systematic assessment of the mechanism of action landscape of glue compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3541.

Abstract A056: Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a low survival rate. A lack of durable responses to chemotherapy renders its treatment particularly challenging and largely contributes to the devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDA therapy, but resistance remains a major hurdle in clinical care. Multiple mechanisms of chemoresistance have been attributed to rewired metabolic pathways in PDA cells. Accordingly, we hypothesized that altered metabolism in gemcitabine resistance represents a therapeutic vulnerability that can be targeted to improve response to treatment. To investigate metabolic vulnerabilities in gemcitabine resistance, we generated gemcitabine resistant murine PDA cell lines and assembled patient-derived gemcitabine high versus low responder organoids. Transcriptomic profiling revealed a downregulation of the mevalonate biosynthesis pathway and its rate-limiting enzyme, HMG-CoA reductase, upon the acquisition of gemcitabine resistance. Upregulation of this pathway has been proposed as a primary resistance mechanism to statins, HMG-CoA reductase inhibitors that are frequently prescribed to treat patients with hyperlipidemia. Accordingly, we postulated that statins would be more potent in gemcitabine resistant PDA cells than in their sensitive counterparts. Indeed, resistant cells were exquisitely susceptible to inhibition of the mevalonate pathway, an observation consistent across multiple clinically available statins. Downstream rescue experiments suggested that the main impact of blocking the mevalonate biosynthesis pathway is through lowered levels of geranylgeranyl pyrophosphate and reduced protein geranylation. To validate our findings in vivo, we implanted gemcitabine resistant murine PDA cells into syngeneic mice that were fed with a modified diet precluding geranylgeraniol. Here, the treatment combination gemcitabine and pitavastatin inhibited tumor growth of resistant allografts. Collectively, these data suggest that targeting the HMG-CoA reductase is a metabolic vulnerability that is gained in PDA cells upon the acquisition of gemcitabine resistance. The combination therapy gemcitabine and pitavastatin, two widely used compounds in patients, has potential to translate into a clinical benefit and improve survival in this deadly disease. Citation Format: Alica K. Beutel, Sabrina Calderon, Ethan Nghiem, Rima Singh, Cecily Anaraki, Kevin Gulay, Herve Tiriac, Alexander Kleger, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Dennis Juarez, David Fruman, Christopher Halbrook. Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A056.

Abstract A095: ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition

Abstract Pancreatic Ductal Adenocarcinoma (PDA) can be characterized by two distinct transcriptional subtypes: classical and basal. The basal PDA subtype is more aggressive and has the worst overall survival. We have previously shown that the histone deacetylase (HDAC) Sirtuin 6 (SIRT6), a marker of the classical PDA subtype, can control sensitivity to CDK7 inhibitors. Interestingly, SIRT6 is part of the KAP1 repressive complex where it functions as an HDAC. This complex functions to maintain heterochromatin at specific regions of the genome by removing marks of open chromatin and installing marks of repressive chromatin with histone methyltransferases (HMT) and DNA methyltransferases (DNMT). The complex relies on a KRAB-Zinc Finger protein to bind DNA directly and modify chromatin at those regions. Since we found that SIRT6 can control sensitivity to CDK7 inhibition, we hypothesized that the KAP1 repressive complex is crucial for maintaining subtype-specific chromatin states and that manipulation of any part of this complex could alter subtype, thereby changing sensitivity to CDK7 inhibition. In a survey of basal and classical PDA cell lines, we found that the KRAB-Zinc Finger ZNF274 showed substantial differential expression, similar to SIRT6, and correlated with overall patient survival. We validated ZNF274 expression in PDA cell lines and organoids by western blot and immunofluorescence and found that classical PDA expressed high levels of ZNF274. Next, we investigated how loss of ZNF274 would affect classical PDA cells and found that knockdown of this protein induced an epithelial-to-mesenchymal (EMT) transition through increased ZEB1 expression. We analyzed protein and RNA expression of more EMT regulators and identified morphological changes representative of EMT. Therefore, this induction of EMT upon loss of ZNF274 could be initiating a subtype switch from classical PDA to basal. To determine if loss of ZNF274 and induction of the mesenchymal state could sensitize cells to CDK7 inhibition as we have previously shown, we performed ZNF274 knockdown in classical PDA and saw a dramatic increase in sensitivity to CDK7 inhibitors. Therefore, we have shown the KAP1 repressive complex to be important in regulating cell state and sensitivity of classical PDA to CDK7 inhibitors which we hope to exploit to improve patient responses to CDK7 inhibition therapy. Citation Format: Jessica Gianopulos, Adrianne Wallace-Povirk, Sita Kugel. ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A095.

Abstract 3276: Tumor cell-intrinsic PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer

Abstract Pancreatic adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the US partly because of its resistance to conventional chemotherapies. Immunotherapies that improve survival in many cancers, almost universally fail in PDA. The resistance to immune checkpoint blockade is at least partially explained by the lack of T cells in the tumor microenvironment (TME) in PDA. We have previously demonstrated that tumor cell-derived prostaglandin E2 (PGE2) is one of the tumor intrinsic factors that creates/supports immunosuppressive TME in PDA presumably through its paracrine effect on the stromal cells. In the current study, we investigate the role of autocrine PGE2 signaling through its cognate EP4 receptor in shaping the T cell low, myeloid cell rich PDA TME. The knockdown (EP4 KD) or knockout (EP4 KO) of the receptors on KrasG12D/p53R172H/YFP/PdxCre (KPCY) tumor cells was sufficient to suppress or abolish the growth of implanted tumors, respectively (control vs EP4 KD, p=0.01, and control vs EP4 KO, p<0.0001). The rejection of the EP4 KO PDA cell lines was T cell dependent as it did not happen in hosts depleted of CD4+ and CD8+ T cells. Upon rechallenge, 80-90% of mice that rejected the primary EP4 KO tumors were able to reject the control, EP4-sufficient tumors in a T cell-dependent manner. While EP4 KO tumors were universally rejected by wild-type (WT) or EP4 global KO (KOgl) hosts, control cell lines formed tumors and grew in both hosts albeit with significantly slower growth in EP4 KOgl hosts (p<0.0001). The TME analysis revealed changes in the T cell presence, subtypes, and functional state in EP4 KO tumors demonstrating more T cell inflamed TME with increased proportions of central memory CD4+ and CD8+ cells (p=0.02 both) along with downregulation of exhaustion markers PD-1 (p=0.02) and CD39 (p=0.009) on CD4+ and CD8+ cells, respectively. Deletion of EP4 on tumor cells changed the systemic anti-tumor immunity by inducing T cell proliferation in lymph nodes (EP4 KO vs control, Ki67+CD8+ p<0.0001 and Ki67+CD4+ p=0.003) and depleting gMDSC population in the spleens of EP4 KO tumor bearing mice (p<0.0001). RNAseq analysis of tumor cells (cultured and in vivo) as well as bulk tumors identified TNFa, IFNa, and IFNg pathways as top upregulated ones in EP4 KO tumors while TGFb and Myc pathways were among the significantly downregulated pathways. The study demonstrates a primary role of tumor cell PGE2-EP4 signaling in creating immunosuppressive TME in PDA suggesting EP4 blockade as a novel approach in treatment of pancreatic cancer. Citation Format: Nune Markosyan, Charu Arora, Liz Quinones, Il-Kyu Kim, Nikhil Joshi, Noah Cheng, John Tobias, Ben Stanger, Robert Vonderheide. Tumor cell-intrinsic PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3276.

Abstract B075: Sirtuin 6 histone deacetylase is required for the integrated stress response and resistance to inhibition of transcriptional cyclin dependent kinases in Pancreatic Ductal Adenocarcinoma

Abstract Pancreatic Ductal Adenocarcinoma (PDA) can be characterized by two distinct transcriptional subtypes: Classical and Basal-like. The basal PDA subtype is more aggressive and has the worst overall survival. Previous work has shown that Sirtuin 6 histone deacetylase (SIRT6) acts as a tumor suppressor and cooperates with oncogenic KRAS in GEMM models of PDA. Our study identifies SIRT6 as a biomarker for basal PDA and investigates the underlying sensitivity of basal PDA to inhibition of transcriptional cyclin dependent kinases (CDKs). Through analysis of data from hundreds of human PDA tumors, we identified that low SIRT6 expression correlates with basal PDA while the converse is true for classical PDA. Using many in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts of PDA, we also discovered that basal PDA is uniquely sensitive to the covalent CDK7/12/13 inhibitor THZ1 as well as other inhibitors of transcriptional CDKs. Importantly, removal of SIRT6 can sensitize SIRT6 high/classical PDA to THZ1. Further investigation identified that SIRT6 low/basal PDA has an inactivated Integrated Stress Response (ISR), which is primarily driven by ATF4. To determine how loss of SIRT6 leads to an inability to activate the ISR, we have integrated use of human PDA cell lines, and organoids as well as murine PDA GEMMs where SIRT6 has been deleted or downregulated. We uncovered that SIRT6 regulates the ISR through control of ATF4 translation, specifically through a 3’ UTR open reading frame (uORF) dependent mechanism. To determine whether ISR activation could protect basal PDA cells from transcriptional CDK inhibition, we manipulated expression of ISR pathway components. We found that activation of the ISR in SIRT6 low/basal PDA reduces sensitivity to THZ1, while inactivation of the ISR sensitizes SIRT6 high/classical PDA to this inhibitor. Interestingly, both basal and classical PDA exhibit increased phosphorylation of eIF2a upon inhibition of transcriptional CDKs, which typically indicates activation of the ISR in response to stress. However, this activation of the ISR remains incomplete since ATF4 translation is not upregulated in basal PDA in the absence of SIRT6. Therefore, we discovered that loss of SIRT6 sensitizes basal PDA to inhibition of transcriptional CDKs through an inability to launch a functional ISR response. Furthermore, we have uncovered an important biomarker which controls a stress-induced transcriptional program that may be exploited with targeted therapies in a particularly aggressive PDA subtype. Citation Format: Jessica Gianopulos, Nithya Kartha, Zachary Schrank, Stephanie Dobersch, Sarah Cavender, Bryan Kynnap, Adrianne Wallace-Povirk, Cynthia Wladyka, Juan Santana, Jaeseung C. Kim, Angela Yu, Caroline Bridgwater, Kathrin Fuchs, Sarah Dysinger, Aaron Lampano, Faiyaz Notta, David Price, Andrew Hsieh, Sunil Hingorani, Sita Kugel. Sirtuin 6 histone deacetylase is required for the integrated stress response and resistance to inhibition of transcriptional cyclin dependent kinases in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B075.

Abstract IA019: Stromal-epithelial co-evolution and complicity in pancreas cancer

Abstract The robust desmoplasia of PDA is its distinguishing feature and non-malignant components constitute the bulk of the tumor mass. This stromal reaction includes myofibroblasts, inflammatory fibroblasts, endothelial cells, pericytes, and various immune-cell subsets, all embedded within a dense and complex extracellular matrix (ECM). Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with, or coopt the surrounding cells and signaling processes in its microenvironment. It is proposed that an invasive PDA represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster tumorigenesis. The detailed kinetics and stepwise construction of the pancreas cancer neo-organ suggest that it is governed by a discrete set of organizing rules and principles – and repeated attempts to target its specific components reveal self-regulating mechanisms of resistance. Indeed, many of these cells arise and operate at the behest of oncogenic KRAS, the signature genetic mutation in PDA. These cells, in turn, support and shape the evolving malignancy. It is frequently debated in pancreas and other cancers whether the stroma is “good” or “bad”, tumor-constraining or tumor-promoting. However, because the stroma is neither static nor monolithic, the question is misguided. The stroma is more nuanced: some elements overtly accelerate, and others attenuate, disease progression but most of the cells and processes found in an evolving pancreas cancer are adaptive at some point during its development. In the end, these elements collectively conspire to create a drug- and immune-privileged sanctuary for PDA progression. To fully overcome the extraordinary resistance of this formidable cancer will require parsing the myriad interactions and interdependencies among the various stromal elements and the epithelial PDA cell. Understanding how to combine strategies against these distinct components and processes – which ones to target, in what order and for how long – will be critical, and perhaps necessary, for success and to avoid making matters worse. Citation Format: Sunil R. Hingorani. Stromal-epithelial co-evolution and complicity in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA019.

Abstract 3935: The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease that will soon become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits for this devastating disease, and in the majority of cases, only improve survival by a few months. Moreover, systemic toxicities are a harsh reality of these treatments. FOLFIRINOX is the drug regimen of choice, one component of which is 5-Fluorouracil (5-FU) which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance due, in part, to thymidylate synthase (TS) overexpression. The Gmeiner lab has pioneered the development of polymeric fluoropyrimidines, named F10 and CF10, which unlike 5-FU, are in principle completely converted to the TS inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities and while displaying much stronger anti-cancer activity. Here, we further confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors targeting replication stress, a hallmark of PDA cells. We show that, consistent with our previous studies in PDA cells, CF10 is much more potent as a single agent than 5-FU, by an average 308x fold, and was effective in the nM range (GI50 range 3.13 - 336 nM) in 5 PDA cell lines tested. We also found that CF10 induces increased replication stress as assessed by phosphorylation of ATR, which appears as early as 8 hours after treatment and increases in intensity over 48 hours, consistent with the kinetics of FdU being released from CF10 and incorporated into DNA, a process requiring several hours. Importantly, phosphorylation of ATR induced by CF10 was significantly higher than with 5-FU. This is especially striking because compounds for this assay were used at their IC50 concentrations, with for example MiaPaCA2 cells being exposed to 899 time more 5-FU than CF10, yet at this concentration 5-FU induced less ATR phosphorylation. Further, we find that the activity of CF10, but not 5-FU can be enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 damage checkpoints. Our results indicate CF10 has potential to supersede the established benefit of 5-FU in PDA treatment and indicate novel combination approaches that may be beneficial compared to well-established regimens used currently for 5-FU. Citation Format: Roberto DiNiro, Alex O. Haber, Kang J. Jeong, Soon Y. Park, Gordon B. Mills, William H. Gmeiner, Jonathan R. Brody. The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3935.

Abstract 3139: Disrupting prostaglandin E2 signaling to reverse treatment resistance in cancer

Abstract Pancreatic adenocarcinoma (PDA) accounts for 3% of all cancers in the USA and 7% of all cancer deaths partly because of its resistance to immunotherapy. PDA manifests itself as a desmoplastic, myeloid cell-rich tumor with a notable paucity of T cells. Pathway analysis of the T cell low, immunotherapy resistant mouse PDA cell lines has identified the prostaglandin E2 (PGE2) synthetic pathway as one of the most upregulated ones. We have previously shown that the deletion or pharmacological inhibition of COX-2, the rate-limiting PGE2 synthesis enzyme, slows the tumor growth and synergizes with immunotherapy to further suppress PDA progression. The current study investigates how the disruption of PGE2 signaling through its receptors, EP4 and EP2, can affect PDA. We use EP receptor genetic and pharmacological inhibition models - we disrupt EP signaling on tumor cells only or systemically, test the effects in T cell low, intermediate, and high PDA tumors, alone or in combination with chemo and immunotherapy. EP4 receptor blocker combined with the agonistic CD40 and anti-PD-1 antibodies significantly increased tumor-free survival of the T cell intermediate PDA implanted tumor-bearing (TB) mice (57% tumor-free in treated vs 0% in the control group). The same combination therapy tended to increase the survival in autochthonous tumor-bearing KrasG12D and p53R172H transgenic mice (p=0.08). CRISPR knockout (KO) of the EP4 in the T cell low cell line abolished the growth of subcutaneous (SQ) tumors and significantly slowed the progression of orthotopically implanted tumors (p=0.009 EP4 KO vs control). Treatment of the SQ T cell low TB mice with EP2/EP4 blockers in combination with either anti-PD-1 or chemotherapy slowed the tumor growth compared to the controls (p=0.002 and p=0.004, respectively) and increased the survival (p=0.007 and p=0.002, respectively). A week of combination treatment resulted in changes in the myeloid cell compartment of the TME - an increase in the proportion of M1 macrophages and type 1 conventional dendritic cells with no significant changes in the T cell compartment. The study demonstrates an alternative approach to targeting the PGE2 pathway in tumors and aims to develop a multiprong treatment regimen to reverse the therapy resistance in PDA. Normal 0 false false false EN-US X-NONE X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} <![endif]–> Citation Format: Nune Markosyan, Liz Quinones, Charu Aurora, Nikhil Joshi, Ilkyu Kim, Ben Z. Stanger, Robert H. Vonderheide. Disrupting prostaglandin E2 signaling to reverse treatment resistance in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3139.

Abstract PO-095: A cancer cell-intrinsic GOT2-PPARδ axis suppresses antitumor immunity

Abstract Glutamic-oxaloacetic transaminase 2 (GOT2) encodes a product with dual functions: primarily as a metabolic enzyme in mitochondria but also as a putative fatty acid (FA) binding protein. The purpose of this study is to investigate GOT2 function and FA-binding in PDA carcinogenesis. Depletion of GOT2 expression with CRISPR-Cas9 or shRNA in human and murine PDA cell lines shows no proliferation defects in vitro. However, GOT2-depleted cells orthotopically implanted in immunocompetent hosts fail to form large tumors. Analysis of cancer cell proliferation shows no difference between control and knockout (KO) tumors, indicating proliferation is not affected by GOT2 in vivo. Genes negatively correlated with GOT2 expression in human PDA reveal ontology clusters associated with adaptive immune response, which suggests an immune-modulatory role of GOT2. Quantitation of immune markers using conventional and multiplex immunohistochemistry confirmed enhanced immune cell infiltration in KO tumors. Inhibition of T cells with blocking antibodies rescued the growth of GOT2 KO tumors, further validating the role of GOT2 in mediating adaptive tumor immunity. In addition to its known mitochondrial and plasma membrane localization, GOT2 expression was observed in the nuclei of PDA cells. It was hypothesized that nuclear GOT2 can deliver FA-ligand to activate PPARs (peroxisome proliferator activator receptor), a class of ligand-activated transcription factors with tumor-promoting properties; specifically, the ubiquitously expressed PPARδ. Analysis of human PDA RNA-seq data shows a significant positive correlation between GOT2 and PPARδ target genes. GOT2-dependent PPARδ activation in PDA cells was confirmed in vitro. Computational modeling of the crystal structure of GOT2 revealed a suitable arachidonic acid (AA) docking site, a known PPARδ ligand. Lipid binding assays of purified protein confirmed direct GOT2-AA binding. The FA docking site of GOT2 was mutated and KO cells were reconstituted with wild type and mutant GOT2. GOT2 mutant cells, compared to wild-type GOT2 cells, showed reduced PPARδ activity, nuclear localization, and interaction with PPARδ. In vivo, mutant GOT2 increased immune cell infiltration. Lastly, the rescue of PPARδ activity in GOT2 KO tumors restores the formation of large tumors with similar immune microenvironments to control tumors. We conclude that the enzymatic function of GOT2 is dispensable for PDA proliferation. However, GOT2 direct FA binding enhances activation of PPARδ to promote an immune-suppressed microenvironment. This non-canonical function of GOT2 can be further explored to elucidate mechanisms of immune evasion in PDA and aid in the development of efficient immunotherapies to improve disease outcomes. Citation Format: Jaime Abrego, Hannah Sanford-Crane, Chet Oon, Xu Xiao, Courtney Betts, Duanchen Sun, Shanthi Nagarajan, Zheng Xia, Lisa Coussens, Peter Tontonoz, Mara Sherman. A cancer cell-intrinsic GOT2-PPARδ axis suppresses antitumor immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-095.

Targeting DNA Damage Repair Pathways in Pancreatic Adenocarcinoma.

Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Abstract A45: Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers

Abstract Pancreatic ductal adenocarcinoma was responsible for ~43,000 deaths in the USA in 2017 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS. Although the clinical picture remains grim, the mechanisms by which key alterations in tumor suppressors and proto-oncogenes contribute to PDA have been dissected. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis. However, to date, pharmacologic inhibition of this pathway has provided no clinical benefit to PDA patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDA cell lines elicits autophagy, a process of cellular recycling that protects pancreatic cancer cells from the potentially cytotoxic effects of KRAS pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic antiproliferative effects against PDA cell lines in vitro, and promotes regression of xenografted patient-derived PDA tumors in mice. Finally, treatment of a KRAS-mutated PDA patient on a compassionate basis with the combination of trametinib plus hydroxychloroquine resulted in a partial but nonetheless striking disease response. These data suggest that this combination therapy may represent a new strategy to target RAS-driven cancers such as PDA. Citation Format: Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Gullien, Mona Foth, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A45.

Abstract I22: New players and unique features of cancer lysosomes

Abstract Pancreatic ductal adenocarcinoma (PDA) cells and tumors constitutively activate nutrient scavenging pathways, namely, autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material) in order to maintain metabolic homeostasis. Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Our prior work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. PDA tumors are effectively “addicted” to enhanced catabolic activity as blocking lysosome function specifically inhibits in vitro and in vivo growth of PDA cell lines and tumor xenografts with minimal effects on normal cells. How key changes in lysosome composition and content contribute to the aggressive nature of PDA remains an open question. We have optimized methodologies to isolate and purify lysosomes from normal human pancreatic epithelial cells and several established patient-derived PDA cancer cell lines, using affinity-based capture techniques that isolate 50-80% intact lysosomes free of cytoplasm and other contaminating organelles. By systematically implementing lysosome purification from normal, primary, and metastatic PDA tumors combined with mass spectrometry-based proteomics, we have identified both resident and substrate proteins that are uniquely associated with PDA lysosomes. Several cancer-specific lysosomal membrane proteins emerged from this analysis that may endow cancer lysosomes with enhanced functionality, including rapid membrane repair in the face of sustained mechanical and chemical insults. Similarly, we find that PDA lysosomes degrade select cellular proteins to enable dynamic remodeling of the cellular proteome in a manner that favors tumor growth and progression. Collectively, our data provide strong evidence in support of the lysosome as a central mediator of cellular adaptation to stress and promoter of tumorigenesis. Citation Format: Rushika M Perera. New players and unique features of cancer lysosomes [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I22.

Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.

A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism

Mitochondrial pyruvate carrier 1 (MPC-1) appears to be a tumor suppressor. In this study, we determined the regulation of MPC-1 expression by Lysine demethylase 5A (KDM5A) and critical impact of this novel KDM5A/MPC-1 signaling on PDA progression. TCGA database, paired PDA and adjacent normal pancreatic tissues, PDA tissue array and cell lines were used to determine the levels of MPC-1 and KDM5A expression, and their relationship with the clinicopathologic characteristics and overall survival (OS) of PDA patients. Both in vitro and in vivo models were used to determine biologic impacts of MPC-1 and KDM5A on PDA and mitochondrial pyruvate metabolism, and the mechanism underling reduced MPC-1 expression in PDA. The expression of MPC-1 was decreased in PDA cell lines and tissues, and negatively associated with tumor poorer differentiation, lymph nodes metastasis, higher TNM stages, and patients' overall survival (OS). Functional analysis revealed that restored expression of MPC-1 suppressed the growth, invasion, migration, stemness and tumorigenicity. Re-expression of MPC-1 stimulated the mitochondrial pyruvate metabolism and inhibited glycolysis, while MPC-1-specific inhibitor UK5099 attenuated these effects. Furthermore, KDM5A bound directly to MPC-1 promoter region and transcriptionally suppressed the expression of MPC-1 via demethylation H3K4. Consistently, KDM5A expression was elevated in PDA and promoted PDA cell proliferation in vitro and tumor growth in vivo via suppressing the expression of MPC-1. The expression of KDM5A was inversely correlated with that of MPC-1 in PDA. KDM5A/MPC-1 signaling promoted PDA growth, invasion, migration, and stemness via inhibiting mitochondrial pyruvate metabolism. Targeting KDM5A/MPC-1 signaling may be an effective therapeutic strategy for PDA.

Abstract 167: Semaphorin3D signaling in the invasion and metastasis of pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease, with the lowest stage-combined 5-year survival rate of any cancer type at 8%. One major attribute for this poor prognosis is the lack of effective treatments in preventing and controlling metastasis. Previously, our lab has identified the secreted protein Semaphorin3D (Sema3D) to be involved in the invasion and metastasis of PDA. Sema3D is part of the axon guidance gene family, recently been reported to be the most frequently altered gene family in PDA. We have previously found Sema3D interacts with its co-receptors PlexinD1 and Neuropilin-1 to cause increased invasion and metastatic capabilities in PDA cells. We found expression of Sema3D and PlexinD1 increases progressively during PDA development. In addition, tumoral knockdown of Sema3D prolongs survival and reduces metastasis of PDA-bearing mice. Also, Sema3D abundance was found to be significantly associated with human metastatic disease formation. However, the molecular signaling of Sema3D in aiding increased PDA cell invasion and metastasis is unknown. In the present study, we found treatment of mutant KrasG12D PDA, KPC cells, with Sema3D increases the activation of ADP-ribosylation factor 6 (Arf6). Interestingly, mutant KrasG12D has recently been reported to signal with Arf6 causing increased glycolytic metabolic changes. We found treating KPC cells with Sema3D increased glycolytic gene expression and increased tumor cell lactic acid secretion. Blockage of PlexinD1, the Sema3D receptor, with neutralizing antibodies inhibits this increase in glycolytic gene expression. Additionally, Panc02 PDA cells, not expressing mutant Kras, intriguingly do not show increased Arf6 activation after Sema3D treatment, suggesting Sema3D signaling could provide a selective role in mutant Kras expressing cells. Also, we investigated the role of Sema3D-induced increased acidity on tumor associated macrophage polarization. Bone-marrow derived macrophages were polarized to an M1, anti-tumor, or M2, pro-tumor phenotype and co-cultured with KPC cells treated with Sema3D or control protein. Macrophages isolated from the co-culture treated with Sema3D had decreased expression of anti-tumor M1 and increased expression of pro-tumoral M2 polarization markers compared to control. Futhermore, to study Sema3D expression in PDA in vivo, we crossed conditional Sema3D knockout mice to KRASG12D TP53R172H PDX-1-CRE+/+ (KPC) mice to create the KRASG12D TP53R172H Sema3D-/- PDX-1-CRE+/+ KPCS mouse model. Current studies are using the KPCS model to evaluate the role of Sema3D in PDA tumor development and metastasis, as well as, examine changes in tumor associated macrophage polarization. Taken together, this study provides enhanced mechanistic understanding of the role of Sema3D in aiding tumor progression and metastasis and, provides support for targeting the axon guidance pathway for PDA metastasis. Citation Format: Noelle R. Jurcak, Stephen Muth, Kenji Fujiwara, Agnieszka Rucki, Kelly Foley, Adrian Murphy, Elizabeth M. Jaffee, Lei Zheng. Semaphorin3D signaling in the invasion and metastasis of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 167.

Abstract 2183: Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma was responsible for ~43,000 deaths in the USA in 2017 and is the epitome of a recalcitrant cancer driven by an, as yet, pharmacologically intractable oncoprotein, KRAS. Although the clinical picture remains grim, the mechanisms by which key alterations in tumor suppressors and proto-oncogenes contribute to PDA have been dissected. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis. However, to date, pharmacological inhibition of this pathway has provided no clinical benefit to PDA patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDA cell lines elicits autophagy, a process of cellular recycling that protects pancreatic cancer cells from the potentially cytotoxic effects of KRAS pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro, and promotes regression of xenografted patient-derived PDA tumors in mice. Finally, treatment of a PDA patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers such as PDA. Citation Format: Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon. Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2183.

Abstract 1714: Nuclear receptor Nurr1 facilitates pancreatic ductal adenocarcinoma cell survival under metabolic stress

Abstract Background: Pancreatic cancer is lethal and the fourth leading cause of cancer deaths in the United States with a 5-year overall survival rate of 6.7%. The orphan nuclear receptor 4A2 (NR4A2, Nurr1) has been implicated in various cellular processes, including inflammation, vascular remodeling, and cancer as a transcriptional facilitator of tumorigenesis, through its regulation of various proliferation, invasion, and metastasis-associated genes. In the pancreatic cancer context, very little is known about NURR1. Here, we explored the expression, prognostic value, and function of NURR1 in human PDA growth and metastasis. We also investigated the role of NURR1 in regulating pancreatic cancer metabolism. Methods: We analyzed The Cancer Genome Atlas (TCGA) database for PDA and microarray expression data from GEO and examined NURR1 expression in normal pancreatic tissue, primary pancreatic tumors and metastatic tumors by using the R statistical computing environment. Kaplan-Meier analysis were performed to investigate the prognostic significance of NURR1 for PDA. NURR1 levels were depleted with siRNA oligos, and also overexpressed with NURR1 cDNA. Following characterization of NURR1 expression, we performed a cell proliferation (XTT) assay and assessed anchorage-independence over a 3-week period by soft agar colony formation assay under normal condition and metabolic stress. Metastatic potential was measured by Matrigel invasion and transwell migration assays. Experiments were performed in MIA PaCa-2, Panc-1 and L3.6pl cell lines. Results: Analysis of messenger RNA (mRNA) expression data from 177 PDA samples from TCGA showed that NURR1 was overexpressed in PDA tissues compared with the pancreatic normal samples (P< 0.001). Kaplan-Meier analysis revealed that 5-year median overall survival (OS) and progression free survival (PFS) were significantly poorer in the NURR1-overexpression group (P= 0.002). Moreover, knockdown of NURR1 significantly reduced PDA cell proliferation, migration, and invasion, whereas NURR1 overexpression resulted in a significant increase in proliferation and migration. In addition, mRNA expression of NURR1 was increased after 12 hours of glucose deprivation in 2 cell lines (vs. 25mM glucose). However, NURR1 depletion impaired survival in low glucose media (5mM) and overexpression of NURR1 had a protective effect under glucose deprivation in Panc-1 cells. Conclusion: NURR1 exhibits a tumor-promoting effect on PDA and NURR1 expression is critical for pancreatic cancer cell survival under glucose deprivation. Our work demonstrates that manipulation of NURR1 expression affects key characteristics of pancreatic tumorigenesis (i.e. proliferation, invasion, and migration). Improved understanding of how NURR1 regulates metabolism in response to stress should uncover novel therapeutic strategies against pancreatic cancer. Note: This abstract was not presented at the meeting. Citation Format: Sneha Harishchandra, Xi Li, Stephen Safe, Mahsa Zarei. Nuclear receptor Nurr1 facilitates pancreatic ductal adenocarcinoma cell survival under metabolic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1714.

Treatment of pancreatic ductal adenocarcinoma with tumor antigen specific-targeted delivery of paclitaxel loaded PLGA nanoparticles

BackgroundPancreatic ductal adenocarcinoma (PDA) remains the most aggressive cancers with a 5-year survival below 10%. Systemic delivery of chemotherapy drugs has severe side effects in patients with PDA and does not significantly improve overall survival rate. It is highly desirable to advance the therapeutic efficacy of chemotherapeutic drugs by targeting their delivery and increasing accumulation at the tumor site. MUC1 is a membrane-tethered glycoprotein that is aberrantly overexpressed in > 80% of PDA thus making it an attractive antigenic target.MethodsPoly lactic-co-glycolic acid nanoparticles (PLGA NPs) conjugated to a tumor specific MUC1 antibody, TAB004, was used as a nanocarrier for targeted delivery into human PDA cell lines in vitro and in PDA tumors in vivo. The PLGA NPs were loaded with fluorescent imaging agents, fluorescein diacetate (FDA) and Nile Red (NR) or isocyanine green (ICG) for in vitro and in vivo imaging respectively or with a chemotherapeutic drug, paclitaxel (PTX) for in vitro cytotoxicity assays. Confocal microscopy was used to visualize internalization of the nanocarrier in vitro in PDA cells with high and low MUC1 expression. The in vivo imaging system (IVIS) was used to visualize in vivo tumor targeting of the nanocarrier. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to determine in vitro cell survival of cells treated with PTX-loaded nanocarrier. One-sided t-test comparing treatment groups at each concentration and two-way ANOVAs comparing internalization of antibody and PLGA nanoparticles.ResultsIn vitro, TAB004-conjugated ICG-nanocarriers were significantly better at internalizing in PDA cells than its non-conjugated counterpart. Similarly, TAB004-conjugated PTX-nanocarriers were significantly more cytotoxic in vitro against PDA cells than its non-conjugated counterpart. In vivo, TAB004-conjugated ICG-nanocarriers showed increased accumulation in the PDA tumor compared to the non-conjugated nanocarrier while sparing normal organs.ConclusionsThe study provides promising data for future development of a novel MUC1-targeted nanocarrier for direct delivery of imaging agents or drugs into the tumor microenvironment.

Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma

ObjectivePancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification...